Citations

AbstractBackgroundThe potential association of long‐term oral corticosteroid (OCS) use with adverse events (AEs) in patients with bullous pemphigoid (BP) is not well characterized in a real‐world setting.ObjectivesTo evaluate the effect of OCS use and treatment duration on the incident AEs in patients with BP.MethodsThis retrospective cohort study used medical and pharmacy claims and patient enrollment data from IQVIA PharMetrics® Plus from 2006−2021. Eligible patients had a diagnosis of BP between 1 January 2006 and 30 June 2020 (≥2 claims for BP ≥ 30 days apart). Patients in the OCS cohort also had a claim for OCS use, ≥7.5 mg daily dose of prednisone or equivalent, and no claims for a nonoral systemic corticosteroid (CS) at any time during the study period. A control cohort of patients with BP not using OCS was also selected. Relative risk ratios were estimated between the incidence of AEs in OCS users with different exposure durations (short‐term, <30 days; medium‐term, 30−90 days; long‐term, >90 days) and nonusers by Poisson regression, after adjusting for age, sex, prior drug use, and baseline Charlson Comorbidity Index score within the follow‐up period.ResultsAt the 1‐year follow‐up, long‐term OCS users had a higher incidence of infections, cataract, osteoporosis, heart failure, depression or anxiety, and diabetes compared with OCS nonusers (p < 0.05). Furthermore, compared with nonusers, long‐term users had increased 1‐year risks (risk ratio; 95% confidence interval) for heart failure (2.27; 1.50−3.44), diabetes (2.05; 1.30−3.24), osteoporosis (1.72; 1.23−2.41), and infection (1.50; 1.13−1.99). Long‐term OCS users also had increased 1‐year risks for heart failure (2.00; 1.21−3.28) and osteoporosis (1.70; 1.16−2.50) compared with short‐term OCS users.ConclusionsLong‐term OCS use (≥7.5 mg) in patients with BP was associated with an increased risk of AEs. Study findings demonstrate a need for steroid‐sparing options with an improved safety profile.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain–behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist’s perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP—efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

AbstractBackgroundRecent CMS billing changes have raised concerns about insurance coverage for deep inferior epigastric perforator (DIEP) flap breast reconstruction. This study compared the costs and utilization of transverse rectus abdominis myocutaneous (TRAM), DIEP, and latissimus dorsi (LD) flaps in breast reconstruction.MethodThe study utilized the National Inpatient Sample database to identify female patients who underwent DIEP, TRAM, and LD flap procedures from 2016 to 2019. Key data such as patient demographics, length of stay, complications, and costs (adjusted to 2021 USD) were analyzed, focusing on differences across the flap types.ResultsA total of 17,770 weighted patient encounters were identified, with the median age being 51. The majority underwent DIEP flaps (73.5%), followed by TRAM (14.2%) and LD (12.1%) flaps. The findings revealed that DIEP and TRAM flaps had a similar length of stay (LOS), while LD flaps typically had a shorter LOS. The total hospital charges to costs using cost‐to‐charge ratio were also comparable between DIEP and TRAM flaps, whereas LD flaps were significantly less expensive. Factors such as income quartile, primary payer of hospitalization, and geographic region significantly influenced flap choice.ConclusionThe study's results appear to contradict the prevailing notion that TRAM flaps are more cost‐effective than DIEP flaps. The total hospital charges to costs using cost‐to‐charge ratio and hospital stays associated with TRAM and DIEP flaps were found to be similar. These findings suggest that changes in the insurance landscape, which may limit the use of DIEP flaps, could undermine patient autonomy while not necessarily reducing healthcare costs. Such policy shifts could favor less costly options like the LD flap, potentially altering the landscape of microvascular breast reconstruction.

AbstractPreviously, lysosomes were primarily referred to as the digestive organelles and recycling centers within cells. Recent discoveries have expanded the lysosomal functional scope and revealed their critical roles in nutrient sensing, epigenetic regulation, plasma membrane repair, lipid transport, ion homeostasis, and cellular stress response. Lysosomal dysfunction is also found to be associated with aging and several diseases. Therefore, function of macroautophagy, a lysosome‐dependent intracellular degradation system, has been identified as one of the updated twelve hallmarks of aging. In this review, we begin by introducing the concept of lysosomal quality control (LQC), which is a cellular machinery that maintains the number, morphology, and function of lysosomes through different processes such as lysosomal biogenesis, reformation, fission, fusion, turnover, lysophagy, exocytosis, and membrane permeabilization and repair. Next, we summarize the results from studies reporting the association between LQC dysregulation and aging/various disorders. Subsequently, we explore the emerging therapeutic strategies that target distinct aspects of LQC for treating diseases and combatting aging. Lastly, we underscore the existing knowledge gap and propose potential avenues for future research.

Abstract Background: Breast cancer (BC) in males represents a rare clinical entity, accounting about 1% of all breast malignancies diagnosed every year. Emerging evidence suggest that a gender medicine approach is critical in the research and treatment of cancer, based on the possibility that sex hormones, molecular differences, immune system, and other factors might play a crucial role in disease management. Here, we characterized molecular and immune differences between male BC (MaBC) and female BC (FeBC) across BC subtypes. Methods: 10,728 BC samples (male, n=137; female, n=10591) were analysed by next-generation sequencing (592, NextSeq; WES, NovaSeq), Whole Transcriptome Sequencing (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) totaled somatic mutations per tumor (high ≥10 mt/MB). Microsatellite-instability (MSI) was tested by IHC and NGS. Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. Real world treatment-associated survival was extracted from insurance claims and calculated from sample collection to last contact using Kaplan-Meier estimates. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q &lt; 0.05). Results: MaBC represented higher HR+/HER2+ (6.61% vs 4.76%), HR+/HER2- (80.17% vs 60.66%) and lower HR-/HER2+ (1.65% vs 3.5%), TNBC (11.57% vs 31.08%) molecular subtypes compared to FeBC. Compared to HR+/HER2+ FeBC, MaBC had higher frequency of CHEK2, RAD51B, TSC1 mutation (Table 1) and RARα (100% vs 13.61%), DAXX (10% vs 0.16%) copy number alteration (all p &lt; 0.05). HR+/HER2- MaBC had higher frequency of BRCA2, FOXA1, CREBBP, FLCN mutation (Table 1), and FGF3 (21.62% vs 14.31%), MRE11 (1.75% vs 0.23%), MEN1 (1.75% vs 0.13%) copy number alteration, but lower frequency of TP53, CHD1, ESR1 and AKT1 mutation (Table 1) (all p &lt; 0.05). HR-/HER2+ MaBC had higher frequency of BRCA1 (p &lt; 0.05) mutation (Table 1). Male TNBC had higher frequency of CDKN2A, KMT2D, STK11, ASXL1, MYC, NF2, PPM1D, WT1, EPHA2, AMER1, ARHGAP35 mutation (Table 1) and BCL6 (4.35% vs 0.05%) copy number alteration, but lower frequency of TP53 mutation (all p &lt; 0.05) (Table 1). MaBC had higher AR protein expression (82.5% vs 60%) but lower frequency of fusion variant-AR (0.7% vs 3.9%) (all p &lt; 0.05) compared to FeBC. There was no difference in TMB high (7.1% vs 8.4%, p = 0.5) and dMMR/MSI-H (1.8% vs 0.8%, p = 0.1). Analysis of inferred immune cell infiltrates showed that MaBC had increased immune cell infiltration of B cells (5.8% vs 5.3%) and M2 Mφ (4.9% vs 4.3%), but decreased infiltration of DC (2% vs 2.6%) (all p &lt; 0.05). MaBC had increased expression of MHC class II gene HLA-DQB2 (FC: 1.3), but decreased expression of immune-related genes CD274 (FC: 1.2), IDO (FC: 1.4), IL1A (FC: 1.3) and IL12A (FC: 1.5) (all p &lt; 0.05). Correlative analyses with survival will be presented at the meeting. Conclusions: These data indicate that MaBC has a differential mutational frequency, copy number alteration, immune gene expression and immune cell infiltration and overall survival compared to their FeBC counterparts. A better understanding of these sex-based differences with additional research may help inform disease outcomes, provide a rationale for tailored therapeutic approaches and design future treatments. Table 1. Mutation frequency in male and female breast cancer Citation Format: Dario Trapani, Sachin Deshmukh, Sharon Wu, Joanne Xiu, Phil Walker, Pooja Advani, Nancy Lin, Giuseppe Curigliano, Stephanie Graff, Chadi Nabhan, George Sledge Jr, Sara Tolaney, Jose Leone. Molecular and immunological landscape of sex-based differences in breast cancer: a distinct disease in men [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS13-09.

Abstract BACKGROUND: Anti-HER2 therapies have transformed the trajectory for patients with HER2-positive (HER2+) MBC. A subset of patients with HER2+ MBC do exceptionally well and remain on maintenance anti-HER2 therapy for many years. However, current therapy is non-curative and patients are treated indefinitely. While these therapies often are well-tolerated, they may cause significant toxicities, are expensive, and typically require frequent infusion and provider visits. Case reports and retrospective series demonstrate that some patients may do well after stopping anti-HER2 treatment. We currently lack prospective data on the likelihood of clinical impact of successful treatment discontinuation, outcomes among patients who progress and restart HER2-directed therapy, and tools to predict who may safely stop therapy. In this study, we will enroll pts with an exceptional response to anti-HER2 therapy. Pts may elect to either continue or stop anti-HER2 therapy and will be followed clinically and radiographically on a protocol-specified schedule. Considering the central role of patients in choosing the study intervention arm, and the unique nature of stopping therapy as a treatment intervention, patient advocates have been deeply involved in the study design to ensure patient concerns are being heard and addressed. We will retrospectively assess minimal residual disease (MRD), measured in plasma, as a biomarker of ongoing response, in a step toward shifting the treatment paradigm for pts with HER2+ MBC. METHODS: STOP-HER2 is a prospective, non-randomized, phase II, multicenter study of either continuation (cohort 1) or cessation (cohort 2) of anti-HER2 therapy in exceptional responders with HER2+ MBC. Eligible patients must have biopsy-proven HER2+ MBC by ASCO/CAP guidelines and must have been receiving first-line anti-HER2 therapy for MBC for at least 3 years without evidence of progressive disease (PD) as determined by the treating investigator. Patients with prior brain-only PD or oligo-PD outside the brain are eligible at least 2 years after local treatment to the central nervous system (CNS) and in absence of subsequent PD. Up to fifty-two participants will be enrolled into cohort 2, and an additional thirty participants enrolled into the cohort 1, at 10 US sites within the Translational Breast Cancer Research Consortium. Co-primary endpoints are the 1-year progression-free survival (PFS) in cohorts 2 and 1, separately. Secondary endpoints include the clinical benefit rate upon re-initiation of anti-HER2 therapy for patients in cohort 2 experiencing PD after treatment discontinuation; and 3-year overall survival in both cohorts. Correlative endpoints include MRD status at baseline and the correlation between MRD dynamics and outcomes. Patient-reported outcomes will be collected and analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, and decision regret. The study will use a two-stage design to assess the primary objective of estimating the rate of participants who are free of progression at one year after discontinuing anti-HER2 therapy. If 50% or less are free of progression at one year, stopping HER2 therapy would not be considered a viable treatment plan (null hypothesis). The study is designed to have 80% power to reject the null hypothesis at the 10% type I error rate when 68% of exceptional responders are free of progression at one year after stopping HER2 therapy. STOP-HER2 began enrollment in Q2 2023 (NCT05721248). Citation Format: Heather Parsons, Kathryn Ruddy, Stefania Morganti, Karen Smith, Victoria Attaya, Eliza Kallfelz, Michelle DeMeo, Jamie LaScala, Shirley Mertz, Teri Pollastro, Patricia Spears, Adam Brufsky, Chau Dang, Susan Dent, Ahmed Elkhanany, WIlliam Gwin, Ciara O'Sullivan, Kathy Miller, Sara Nunnery, Elaine Walsh, Anna Maria Storniolo, Sara Tolaney, Nabihah Tayob, Antonio Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy Lin. The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-01.

Abstract Background In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43–1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61–1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

Purpose of review Pediatric obesity is a growing concern globally. Patients with a history of overweight/obesity often experience stigmatization, especially in the healthcare setting, and are at increased risk of developing psychological comorbidities including eating disorders. This review appraises the most recent studies evaluating eating disorder risk in youth undergoing treatment for obesity, identifies gaps in the literature, and offers practical guidelines to pediatric providers regarding the management of this population. Recent findings Recent studies suggest that structured weight management programs may decrease the risk of and/or improve symptoms of certain eating disorders such as binge eating disorder and bulimia nervosa. There is a paucity of research on some components of obesity management such as obesity pharmacotherapeutics and eating disorder risk. Summary Children and adolescents with obesity are a psychologically vulnerable population with increased risk for the development of eating disorders. Further study is needed to evaluate general risk in the setting of specialized and primary care obesity interventions and develop appropriate screening and mitigation tools. Some evidence-based strategies can aid pediatric providers in both weight management and eating disorder prevention and risk assessment.